US11753406B2 - Salts of a PD-1/PD-L1 inhibitor - Google Patents

Salts of a PD-1/PD-L1 inhibitor Download PDF

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US11753406B2
US11753406B2 US16/987,557 US202016987557A US11753406B2 US 11753406 B2 US11753406 B2 US 11753406B2 US 202016987557 A US202016987557 A US 202016987557A US 11753406 B2 US11753406 B2 US 11753406B2
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salt
compound
cancer
acid salt
xrpd
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US20210040090A1 (en
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Zhongjiang Jia
Pingli Liu
David J. Meloni
Yongchun Pan
Yongzhong Wu
Jiacheng Zhou
Qun Li
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Incyte Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This application relates to salt forms of the PD-1/PD-L1 inhibitor (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, including methods of preparation thereof, where the compound is useful in the treatment of various diseases including infectious diseases and cancer.
  • the immune system plays an important role in controlling and eradicating diseases such as cancer.
  • cancer cells often develop strategies to evade or to suppress the immune system in order to favor their growth.
  • One such mechanism is altering the expression of co-stimulatory and co-inhibitory molecules expressed on immune cells (Postow et al, J. Clinical Oncology 2015, 1-9). Blocking the signaling of an inhibitory immune checkpoint, such as PD-1, has proven to be a promising and effective treatment modality.
  • PD-1 Programmed cell death-1
  • CD279 is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells, and macrophages (Greenwald et al, Annu. Rev. Immunol 2005, 23:515-548; Okazaki and Honjo, Trends Immunol 2006, (4):195-201). It functions as an intrinsic negative feedback system to prevent the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance.
  • PD-1 is also known to play a critical role in the suppression of antigen-specific T cell response in diseases like cancer and viral infection (Sharpe et al, Nat Immunol 2007 8, 239-245; Postow et al, J. Clinical Oncol 2015, 1-9).
  • the structure of PD-1 consists of an extracellular immunoglobulin variable-like domain followed by a transmembrane region and an intracellular domain (Parry et al, Mol Cell Biol 2005, 9543-9553).
  • the intracellular domain contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates T cell receptor-mediated signals.
  • PD-1 has two ligands, PD-L1 and PD-L2 (Parry et al, Mol Cell Biol 2005, 9543-9553; Latchman et al, Nat Immunol 2001, 2, 261-268), and they differ in their expression patterns.
  • PD-L1 protein is upregulated on macrophages and dendritic cells in response to lipopolysaccharide and GM-CSF treatment, and on T cells and B cells upon T cell receptor and B cell receptor signaling. PD-L1 is also highly expressed on almost all tumor cells, and the expression is further increased after IFN- ⁇ treatment (Iwai et al, PNAS2002, 99(19):12293-7; Blank et al, Cancer Res 2004, 64(3):1140-5).
  • tumor PD-L1 expression status has been shown to be prognostic in multiple tumor types (Wang et al, Eur J Surg Oncol 2015; Huang et al, Oncol Rep 2015; Sabatier et al, Oncotarget 2015, 6(7): 5449-5464).
  • PD-L2 expression in contrast, is more restricted and is expressed mainly by dendritic cells (Nakae et al, J Immunol 2006, 177:566-73).
  • Ligation of PD-1 with its ligands PD-L1 and PD-L2 on T cells delivers a signal that inhibits IL-2 and IFN- ⁇ production, as well as cell proliferation induced upon T cell receptor activation (Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34).
  • the mechanism involves recruitment of SHP-2 or SHP-1 phosphatases to inhibit T cell receptor signaling such as Syk and Lck phosphorylation (Sharpe et al, Nat Immunol 2007, 8, 239-245).
  • Activation of the PD-1 signaling axis also attenuates PKC- ⁇ activation loop phosphorylation, which is necessary for the activation of NF- ⁇ B and AP1 pathways, and for cytokine production such as IL-2, IFN- ⁇ and TNF (Sharpe et al, Nat Immunol 2007, 8, 239-245; Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34).
  • PD-1-deficient mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy (Nishimura et al, Immunity 1999, 11:141-151; Nishimura et al, Science 2001, 291:319-322).
  • LCMV model of chronic infection it has been shown that PD-1/PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus-specific CD8 T cells (Barber et al, Nature 2006, 439, 682-7).
  • the present disclosure is directed to salts of (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid.
  • the present disclosure is further directed to the mono-hydrobromic acid salt, the mono-oxalic acid salt, the mono-hydrochloric acid salt, the mono-L-tartaric acid salt, the di-hydrobromic acid salt, the di-oxalic acid salt, the L-tartaric acid salt (1:1.5), the hydrochloric acid salt (1:1.7), the mono-malonic acid salt, the phosphoric acid salt ( ⁇ 1:3), and the phosphoric acid salt ( ⁇ 1:2) of (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid.
  • the present disclosure is further directed to crystalline forms of the salts described herein.
  • the present disclosure is further directed to pharmaceutical compositions comprising a salt or crystalline form described herein, and at least one pharmaceutically acceptable carrier or excipient.
  • the present disclosure is further directed to solid dosage forms comprising the pharmaceutical compositions.
  • the present disclosure is further directed to a method of inhibiting PD-1/PD-L1 interaction comprising administering to a patient the salts and crystalline forms described herein.
  • the present disclosure also provides uses of the salts and crystalline forms described herein in the manufacture of a medicament for use in inhibiting PD-1/PD-L1 interaction.
  • the present disclosure also provides the salts and crystalline forms described herein for use in inhibiting PD-1/PD-L1 interaction.
  • the present disclosure is further directed to treating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction comprising administering to a patient the salts and crystalline forms described herein.
  • the present disclosure also provides uses of the salts and crystalline forms described herein in the manufacture of a medicament for use in treating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction.
  • the present disclosure also provides the salts and crystalline forms described herein for use in treating a disease or disorder associated with inhibition of PD-1/PD-L1 interaction.
  • the present disclosure is further directed to enhancing, stimulating and/or increasing the immune response in a patient comprising administering to a patient the salts and crystalline forms described herein.
  • the present disclosure also provides uses of the salts and crystalline forms described herein in the manufacture of a medicament for use in enhancing, stimulating and/or increasing the immune response in a patient.
  • the present disclosure also provides the salts and crystalline forms described herein for use in enhancing, stimulating and/or increasing the immune response in a patient.
  • the present invention is further directed to processes for preparing the salts and crystalline forms described herein.
  • FIG. 1 shows an XRPD pattern of Compound 1 mono-hydrobromic acid salt.
  • FIG. 2 shows an XRPD pattern of Compound 1 mono-hydrobromic acid salt prepared by an alternative method.
  • FIG. 3 shows an XRPD pattern of Compound 1 mono-oxalic acid salt.
  • FIG. 4 shows a TGA thermogram of Compound 1 mono-oxalic acid salt.
  • FIG. 5 shows an XRPD pattern of Compound 1 mono-hydrochloric acid salt.
  • FIG. 6 shows an XRPD pattern of Compound 1 L-tartaric acid salt (1:1.5).
  • FIG. 7 shows a 1 H NMR of Compound 1 L-tartaric acid salt (1:1.5).
  • FIG. 8 shows an XRPD pattern of two samples of Compound 1 di-hydrobromic acid salt.
  • FIG. 9 shows an XRPD pattern of Compound 1 di-hydrobromic acid salt prepared by an alternative method.
  • FIG. 10 shows an XRPD pattern of Compound 1 di-oxalic acid salt.
  • FIG. 11 shows a DSC thermogram of Compound 1 di-oxalic acid salt.
  • FIG. 12 shows a TGA thermogram of Compound 1 di-oxalic acid salt.
  • FIG. 13 shows an XRPD pattern of Compound 1 L-tartaric acid salt (1:1.7).
  • FIG. 14 shows a 1 H NMR of Compound 1 L-tartaric acid salt (1:1.7).
  • the present disclosure is directed to, inter alia, a salt of (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid (Compound 1), wherein the salt is selected from:
  • the salt of Compound 1 is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrobromic acid salt (Compound 1 hydrobromic acid salt).
  • the Compound 1 hydrobromic acid salt is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid mono-hydrobromic acid salt (Compound 1 mono-hydrobromic acid salt).
  • the Compound 1 hydrobromic acid salt is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid di-hydrobromic acid salt (Compound 1 di-hydrobromic acid salt).
  • Compound 1 mono-hydrobromic acid salt can be prepared by any suitable method for the preparation of hydrobromic acid addition salts.
  • Compound 1 can be combined with hydrobromic acid (e.g., about 1.0 molar eq. or more) in a solvent and the resulting salt can be isolated by filtering the salt from solution.
  • Compound 1 is combined with about 1 to about 2 molar equivalents of hydrobromic acid.
  • Compound 1 is combined with about 1.0 to about 1.5 molar equivalents of hydrobromic acid.
  • Compound 1 is combined with about 1.05 molar equivalents of hydrobromic acid.
  • the solvent can contain any solvent or mixture of solvents capable of at least partially dissolving Compound 1.
  • the solvent contains an alcohol.
  • Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • the solvent contains acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent contains dichloromethane. In some embodiments, the solvent contains tetrahydrofuran.
  • the solvent is a mixture of isopropyl alcohol, methanol, water, and dichloromethane. In some embodiments, the solvent is a mixture of isopropyl alcohol, water, and tetrahydrofuran.
  • the solvent is about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is from about 50° C. to about 80° C. In some embodiments, the temperature is from about 40° C. to about 60° C. In some embodiments, the temperature is from about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C. or about 80° C.
  • the solvent is heated to a temperature that can induce precipitation at a practical rate.
  • precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 12 hours. In some embodiments, precipitation is completed within about 2 hours.
  • the precipitation of Compound 1 mono-hydrobromic acid salt is carried out by filtering the salt from solution.
  • Compound 1 mono-hydrobromic acid salt can be characterized by the X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1 . In some embodiments, Compound 1 mono-hydrobromic acid salt can be characterized by the X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 2 .
  • XRPD X-ray powder diffraction
  • Compound 1 mono-hydrobromic acid salt is amorphous.
  • Compound 1 di-hydrobromic acid salt can be prepared by any suitable method for preparation of hydrobromic acid addition salts.
  • Compound 1 can be combined with hydrobromic acid (e.g., about 2.0 molar eq. or more) in a solvent and the resulting salt can be isolated by filtering the salt from solution.
  • Compound 1 is combined with about 2 to about 3 molar equivalents of hydrobromic acid.
  • Compound 1 is combined with about 2.0 to about 2.5 molar equivalents of hydrobromic acid.
  • Compound 1 is combined with about 2.3 molar equivalents of hydrobromic acid.
  • Compound 1 is combined with about 2.05 molar equivalents of hydrobromic acid.
  • the solvent can contain any solvent or mixture of solvents capable of at least partially dissolving Compound 1.
  • the solvent contains an alcohol.
  • Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • the solvent contains acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent contains methanol. In some embodiments, the solvent contains tetrahydrofuran.
  • the solvent is a mixture of isopropyl alcohol, water and methanol. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is a mixture of isopropyl alcohol, water and tetrahydrofuran.
  • the solvent is about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is from about 50° C. to about 80° C. In some embodiments, the temperature is from about 40° C. to about 60° C. In some embodiments, the temperature is from about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C. or about 80° C.
  • the solvent is heated to a temperature that can induce precipitation at a practical rate.
  • precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature.
  • the precipitation is completed within about 16 hours.
  • the precipitation is completed within about 12 hours.
  • the precipitation is completed within about 2.5 hours.
  • the precipitation and of the di-hydrobromic acid salt is carried out by filtering the salt from solution.
  • Compound 1 di-hydrobromic acid salt can be characterized by the X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 8 . In some embodiments, Compound 1 di-hydrobromic acid salt can be characterized by the X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 9 .
  • Compound 1 di-hydrobromic acid salt is amorphous.
  • the salt of Compound 1 is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid oxalic acid salt (Compound 1 oxalic acid salt).
  • the Compound 1 oxalic acid salt is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid mono-oxalic acid salt (Compound 1 mono-oxalic acid salt).
  • the Compound 1 oxalic acid salt is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid di-oxalic acid salt (Compound 1 di-oxalic acid salt).
  • Compound 1 mono-oxalic acid salt can be prepared by any suitable method for preparation of oxalic acid addition salts.
  • Compound 1 can be combined with oxalic acid (e.g., about 1.0 molar eq. or more) in a solvent and the resulting salt can be isolated by filtering the salt from solution.
  • Compound 1 is combined with about 1 to about 2 molar equivalents of oxalic acid.
  • Compound 1 is combined with about 1.0 to about 1.5 molar equivalents of oxalic acid.
  • Compound 1 is combined with about 1.05 molar equivalents of oxalic acid.
  • Compound 1 is combined with about 1.1 molar equivalents of oxalic acid.
  • the solvent can contain any solvent or mixture of solvents capable of at least partially dissolving Compound 1.
  • the solvent contains an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • the solvent contains acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propan
  • the solvent is tetrahydrofuran. In some embodiments, the solvent is a mixture of acetone, methanol and dichloromethane.
  • the solvent is about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is from about 50° C. to about 80° C. In some embodiments, the temperature is from about 40° C. to about 60° C. In some embodiments, the temperature is from about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C. or about 80° C.
  • the solvent is heated to a temperature that can induce precipitation at a practical rate.
  • precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature.
  • the precipitation is completed within about 2 hours. In some embodiments, the precipitation is completed within about 90 minutes.
  • the precipitation of the mono-oxalic acid salt is carried out by filtering the salt from solution.
  • Compound 1 mono-oxalic acid salt can be characterized by the X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 3 .
  • Compound 1 mono-oxalic acid salt can be characterized by the thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 4 .
  • Compound 1 mono-oxalic acid salt is amorphous.
  • Compound 1 di-oxalic acid salt can be prepared by any suitable method for preparation of oxalic acid addition salts.
  • Compound 1 can be combined with oxalic acid (e.g., about 2.0 molar eq. or more) in a solvent and the resulting salt can be isolated by filtering the salt from solution.
  • Compound 1 is combined with about 2 to about 3 molar equivalents of oxalic acid.
  • Compound 1 is combined with about 2.0 to about 2.5 molar equivalents of oxalic acid.
  • Compound 1 is combined with about 2.05 molar equivalents of oxalic acid.
  • the solvent can contain any solvent or mixture of solvents capable of at least partially dissolving Compound 1.
  • the solvent contains an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • the solvent contains acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propan
  • the solvent is tetrahydrofuran.
  • the solvent is about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is from about 50° C. to about 80° C. In some embodiments, the temperature is from about 40° C. to about 60° C. In some embodiments, the temperature is from about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C. or about 80° C.
  • the solvent is heated to a temperature that can induce precipitation and/or crystallization at a practical rate.
  • precipitation and/or crystallization is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation/crystallizing solvent and temperature. In some embodiments, the precipitation and/or crystallization is completed within about 2 hours.
  • the precipitation and/or crystallization of the di-oxalic acid salt is carried out by filtering the salt from solution.
  • Compound 1 di-oxalic acid salt can be characterized by the X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 10 .
  • XRPD X-ray powder diffraction
  • Compound 1 di-oxalic acid salt has a characteristic X-ray powder diffraction (XRPD) peak at 7.0 ⁇ 0.2 degrees 2-theta. In some embodiments, Compound 1 di-oxalic acid salt has a characteristic X-ray powder diffraction (XRPD) peak at 11.4 ⁇ 0.2 degrees 2-theta. In some embodiments, Compound 1 di-oxalic acid salt has a characteristic X-ray powder diffraction (XRPD) peak at 13.2 ⁇ 0.2 degrees 2-theta. In some embodiments, Compound 1 di-oxalic acid salt has a characteristic X-ray powder diffraction (XRPD) peak at 14.9 ⁇ 0.2 degrees 2-theta. In some embodiments, Compound 1 di-oxalic acid salt has a characteristic X-ray powder diffraction (XRPD) peak at 17.0 ⁇ 0.2 degrees 2-theta.
  • XRPD characteristic X-ray powder diffraction
  • the di-oxalic acid salt of Compound 1 has characteristic X-ray powder diffraction (XRPD) peaks at 7.0 ⁇ 0.2, 11.4 ⁇ 0.2, and 14.9 ⁇ 0.2 degrees 2-theta. In some embodiments, the di-oxalic acid salt of Compound 1 has characteristic X-ray powder diffraction (XRPD) peaks at 7.0 ⁇ 0.2, 11.4 ⁇ 0.2, 14.9 ⁇ 0.2, and 17.0 ⁇ 0.2 degrees 2-theta. In some embodiments, the di-oxalic acid salt of Compound 1 has characteristic X-ray powder diffraction (XRPD) peaks at 7.0 ⁇ 0.2, 11.4 ⁇ 0.2, 13.2 ⁇ 0.2, 14.9 ⁇ 0.2, and 17.0 ⁇ 0.2 degrees 2-theta.
  • XRPD X-ray powder diffraction
  • Compound 1 di-oxalic acid salt has at least one X-ray powder diffraction (XRPD) peak selected from 7.0 ⁇ 0.2, 11.4 ⁇ 0.2, 13.2 ⁇ 0.2, 14.9 ⁇ 0.2, and 17.0 ⁇ 0.2 degrees 2-theta. In some embodiments, Compound 1 di-oxalic acid salt has at least two X-ray powder diffraction (XRPD) peaks selected from 7.0 ⁇ 0.2, 11.4 ⁇ 0.2, 13.2 ⁇ 0.2, 14.9 ⁇ 0.2, and 17.0 ⁇ 0.2 degrees 2-theta.
  • XRPD X-ray powder diffraction
  • Compound 1 di-oxalic acid salt has at least three X-ray powder diffraction (XRPD) peaks selected from 7.0 ⁇ 0.2, 11.4 ⁇ 0.2, 13.2 ⁇ 0.2, 14.9 ⁇ 0.2, and 17.0 ⁇ 0.2 degrees 2-theta. In some embodiments, Compound 1 di-oxalic acid salt has at least four X-ray powder diffraction (XRPD) peaks selected from 7.0 ⁇ 0.2, 11.4 ⁇ 0.2, 13.2 ⁇ 0.2, 14.9 ⁇ 0.2, and 17.0 ⁇ 0.2 degrees 2-theta.
  • XRPD X-ray powder diffraction
  • Compound 1 di-oxalic acid salt exhibits a DSC thermogram having an endothermic peak at a temperature of 235 ⁇ 3° C.
  • the di-oxalic acid salt of Compound 1 has a DSC thermogram substantially as depicted in FIG. 11 .
  • the di-oxalic acid salt of Compound 1 has a TGA thermogram substantially as depicted in FIG. 12 .
  • Compound 1 di-oxalic acid salt has at least one characteristic XRPD peak selected from 7.0 ⁇ 0.2, 11.4 ⁇ 0.2, 13.2 ⁇ 0.2, 14.9 ⁇ 0.2, and 17.0 ⁇ 0.2 degrees 2-theta; and the di-oxalic acid salt of Compound 1 exhibits a DSC thermogram having an endothermic peak at a temperature of 235 ⁇ 3° C.
  • Compound 1 di-oxalic acid salt is amorphous. In some embodiments, Compound 1 di-oxalic acid salt is crystalline. In some embodiments, Compound 1 di-oxalic acid salt is a mixture comprising crystalline and amorphous forms.
  • the salt of Compound 1 is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid hydrochloric acid salt (Compound 1 hydrochloric acid salt).
  • the Compound 1 hydrochloric acid salt is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid mono-hydrochloric acid salt (Compound 1 mono-hydrochloric acid salt).
  • the Compound 1 hydrochloric acid salt is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid tri-hydrochloric acid salt (Compound 1 tri-hydrochloric acid salt).
  • Compound 1 mono-hydrochloric acid salt can be prepared by any suitable method for preparation of mono-hydrochloric acid addition salts.
  • Compound 1 can be combined with hydrochloric acid (e.g., about 1.0 molar eq. or more) in a solvent and the resulting salt can be isolated by filtering the salt from solution.
  • hydrochloric acid e.g., about 1.0 molar eq. or more
  • Compound 1 is combined with about 1 to about 2 molar equivalents of hydrochloric acid.
  • Compound 1 is combined with about 1 to about 1.5 molar equivalents of hydrochloric acid.
  • Compound 1 is combined with about 1.05 molar equivalents of hydrochloric acid.
  • the solvent can contain any solvent or mixture of solvents capable of at least partially dissolving Compound 1.
  • the solvent contains an alcohol.
  • Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • the solvent contains acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent contains dichloromethane. In some embodiments, the solvent contains methanol.
  • the solvent is a mixture of isopropanol, water, methanol and dichloromethane. In some embodiments, the solvent is a mixture of isopropanol, water and methanol.
  • the solvent is about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is from about 50° C. to about 80° C. In some embodiments, the temperature is from about 40° C. to about 60° C. In some embodiments, the temperature is from about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C. or about 80° C.
  • the solvent is heated to a temperature that can induce precipitation at a practical rate.
  • precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 12 hours.
  • the precipitation of the mono-hydrochloric acid salt is carried out by filtering the salt from solution.
  • Compound 1 mono-hydrochloric acid salt can be characterized by the X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 5 .
  • XRPD X-ray powder diffraction
  • Compound 1 mono-hydrochloric acid salt is amorphous.
  • Compound 1 tri-hydrochloric acid salt can be prepared by any suitable method for preparation of tri-hydrochloric acid addition salts.
  • Compound 1 can be combined with hydrochloric acid (e.g., about 3.0 molar eq. or more) in a solvent and the resulting salt can be isolated by filtering the salt from solution.
  • hydrochloric acid e.g., about 3.0 molar eq. or more
  • Compound 1 is combined with about 3 to about 5 molar equivalents of hydrochloric acid.
  • Compound 1 is combined with about 3 to about 4 molar equivalents of hydrochloric acid.
  • Compound 1 is combined with about 4 molar equivalents of hydrochloric acid.
  • the solvent can contain any solvent or mixture of solvents capable of at least partially dissolving Compound 1.
  • the solvent contains an alcohol.
  • Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • the solvent contains dioxane, dimethylsulfoxide, acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent contains tetrahydrofuran.
  • the solvent is a mixture of dimethylsulfoxide, tetrahydrofuran and dioxane.
  • the solvent is about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is from about 50° C. to about 80° C. In some embodiments, the temperature is from about 40° C. to about 60° C. In some embodiments, the temperature is from about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C. or about 80° C.
  • the solvent is heated to a temperature that can induce precipitation at a practical rate.
  • precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 12 hours.
  • the precipitation of the tri-hydrochloric acid salt is carried out by filtering the salt from solution.
  • Compound 1 tri-hydrochloric acid salt is amorphous.
  • the salt of Compound 1 is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartaric acid salt (Compound 1 L-tartaric acid salt).
  • the Compound 1 L-tartaric acid salt is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartaric acid salt (1:1.5) (Compound 1 L-tartaric acid salt (1:1.5)), wherein the ratio of Compound 1 to L-tartaric acid is about 1 to 1.5.
  • the Compound 1 L-tartaric acid salt is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid L-tartaric acid salt (1:1.7) (Compound 1 L-tartaric acid salt (1:1.7)), wherein the ratio of Compound 1 to L-tartaric acid is about 1 to 1.7.
  • Compound 1 L-tartaric acid salt (1:1.5) can be prepared by any suitable method for preparation of L-tartaric acid addition salts.
  • Compound 1 can be combined with L-tartaric acid in a solvent and the resulting salt can be isolated by filtering the salt from solution.
  • Compound 1 is combined with about 0.8 to about 2.5 molar equivalents of L-tartaric acid.
  • Compound 1 is combined with about 1.5 to about 2.5 molar equivalents of L-tartaric acid.
  • Compound 1 is combined with about 1.9 to about 2.1 molar equivalents of L-tartaric acid.
  • Compound 1 is combined with about 1.8 to about 2.2 molar equivalents of L-tartaric acid.
  • Compound 1 is combined with about 0.9 to about 1.1 molar equivalents of L-tartaric acid. In certain embodiments, Compound 1 is combined with about 0.8 to about 1.2 molar equivalents of L-tartaric acid. In certain embodiments, Compound 1 is combined with about 0.5 to about 1.5 molar equivalents of L-tartaric acid. In certain embodiments, Compound 1 is combined with about 1.5 to about 2.0 molar equivalents of L-tartaric acid. In certain embodiments, Compound 1 is combined with about 1.5 molar equivalents of L-tartaric acid. In certain embodiments, Compound 1 is combined with about 1.05 molar equivalents of L-tartaric acid. In certain embodiments, Compound 1 is combined with about 2.05 molar equivalents of L-tartaric acid.
  • the solvent can contain any solvent or mixture of solvents capable of at least partially dissolving Compound 1.
  • the solvent contains an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • the solvent contains acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propan
  • the solvent is tetrahydrofuran.
  • the solvent is about room temperature. In some embodiments, the solvent is heated to a temperature of at least about 50° C. In some embodiments, the temperature is from about 50° C. to about 80° C. In some embodiments, the temperature is from about 40° C. to about 60° C. In some embodiments, the temperature is from about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C. or about 80° C.
  • the solvent is heated to a temperature that can induce precipitation at a practical rate.
  • precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 2 hours.
  • the precipitation of the L-tartaric acid salt (1:1.5), in some embodiments, is carried out by filtering the salt from solution.
  • Compound 1 L-tartaric acid salt (1:1.5) can be characterized by the X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 6 .
  • Compound 1 L-tartaric acid salt (1:1.5) can be characterized by the 1 H NMR spectrum substantially as depicted in FIG. 7 .
  • Compound 1 L-tartaric acid salt (1:1.5) is amorphous.
  • L-tartaric acid salt (1:1.7) can be prepared by any suitable method for preparation of L-tartaric acid addition salts.
  • Compound 1 can be combined with L-tartaric acid (e.g., about 1.7 molar eq. or more) in a solvent and the resulting salt can be isolated by filtering the salt from solution.
  • Compound 1 is combined with about 1.7 to about 3 molar equivalents of L-tartaric acid.
  • Compound 1 is combined with about 1.7 to about 2.5 equivalents of molar L-tartaric acid.
  • Compound 1 is combined with about 2.05 molar equivalents of L-tartaric acid.
  • Compound 1 is combined with about 1.7 molar equivalents of L-tartaric acid.
  • the solvent can contain any solvent or mixture of solvents capable of at least partially dissolving Compound 1.
  • the solvent contains an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • the solvent contains acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propan
  • the solvent is tetrahydrofuran.
  • the solvent is about room temperature. In some embodiments, the solvent is heated to a temperature of at least about 50° C. In some embodiments, the temperature is from about 50° C. to about 80° C. In some embodiments, the temperature is from about 40° C. to about 60° C. In some embodiments, the temperature is from about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C. or about 80° C.
  • the solvent is heated to a temperature that can induce precipitation at a practical rate.
  • precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, precipitation is completed within about 2 hours.
  • the precipitation of the L-tartaric acid salt (1:1.7), in some embodiments, is carried out by filtering the salt from solution.
  • Compound 1 L-tartaric acid salt (1:1.7) can be characterized by the X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 13 . In some embodiments, Compound 1 L-tartaric acid salt (1:1.7) can be characterized by the 1 H NMR spectrum substantially as depicted in FIG. 14 .
  • XRPD X-ray powder diffraction
  • Compound 1 L-tartaric acid salt (1:1.7) is amorphous.
  • the salt of Compound 1 is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid malonic acid salt (Compound 1 malonic acid salt).
  • the Compound 1 malonic acid salt is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid mono-malonic acid salt (Compound 1 mono-malonic acid salt).
  • Compound 1 mono-malonic acid salt can be prepared by any suitable method for preparation of mono-malonic acid addition salts.
  • Compound 1 can be combined with malonic acid (e.g., about 1.0 molar eq. or more) in a solvent and the resulting salt can be isolated by filtering the salt from solution.
  • malonic acid e.g., about 1.0 molar eq. or more
  • Compound 1 is combined with about 1 to about 2 molar equivalents of malonic acid.
  • Compound 1 is combined with about 1 to about 1.5 molar equivalents of malonic acid.
  • Compound 1 is combined with about 1.1 molar equivalents of malonic acid.
  • the solvent can contain any solvent or mixture of solvents capable of at least partially dissolving Compound 1.
  • the solvent contains an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, 1-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • the solvent contains acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol
  • the solvent is a mixture of acetone, methanol and dichloromethane.
  • the solvent is about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is from about 50° C. to about 80° C. In some embodiments, the temperature is from about 40° C. to about 60° C. In some embodiments, the temperature is from about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C. or about 80° C.
  • the solvent is heated to a temperature that can induce precipitation at a practical rate.
  • precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature.
  • precipitation is completed within about 1 to about 2 hours. In some embodiments, precipitation is completed within about 90 minutes.
  • the precipitation of the mono-malonic acid salt is carried out by filtering the salt from solution.
  • Compound 1 mono-malonic acid salt is amorphous.
  • the salt of Compound 1 is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphoric acid salt (Compound 1 phosphoric acid salt).
  • the Compound 1 phosphoric acid salt is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphoric acid salt ( ⁇ 1:2) (Compound 1 phosphoric acid salt ( ⁇ 1:2)), wherein the ratio of Compound 1 to phosphoric acid is about 1 to 2.
  • the Compound 1 phosphoric acid salt is (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid phosphoric acid salt ( ⁇ 1:3) (Compound 1 phosphoric acid salt ( ⁇ 1:3) wherein the ratio of Compound 1 to phosphoric acid is about 1 to 3.
  • Compound 1 phosphoric acid salt ( ⁇ 1:2) can be prepared by any suitable method for preparation of phosphoric acid ( ⁇ 1:2) addition salts.
  • Compound 1 can be combined with phosphoric acid (e.g., about 2.0 molar eq. or more) in a solvent and the resulting salt can be isolated by filtering the salt from solution.
  • Compound 1 is combined with about 2 to about 3 molar equivalents of phosphoric acid.
  • Compound 1 is combined with about 2 to about 2.5 molar equivalents of phosphoric acid.
  • Compound 1 is combined with about 2 molar equivalents of phosphoric acid.
  • the solvent can contain any solvent or mixture of solvents capable of at least partially dissolving Compound 1.
  • the solvent contains an alcohol.
  • Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • the solvent contains acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the solvent contains dichloromethane. In some embodiments, the solvent contains acetone.
  • the solvent is a mixture of acetone, methanol and dichloromethane.
  • the solvent is about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is from about 50° C. to about 80° C. In some embodiments, the temperature is from about 40° C. to about 60° C. In some embodiments, the temperature is from about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C. or about 80° C.
  • the solvent is heated to a temperature that can induce precipitation at a practical rate.
  • precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, the precipitation is completed within about 90 minutes.
  • the precipitation of the phosphoric acid salt ( ⁇ 1:2) is carried out by filtering the salt from solution.
  • Compound 1 phosphoric acid salt ( ⁇ 1:2) is amorphous.
  • Compound 1 phosphoric acid salt ( ⁇ 1:3) can be prepared by any suitable method for preparation of phosphoric acid ( ⁇ 1:3) addition salts.
  • Compound 1 can be combined with phosphoric acid (e.g., about 3.0 molar eq. or more) in a solvent and the resulting salt can be isolated by filtering the salt from solution.
  • Compound 1 is combined with about 3 to about 5 molar equivalents of phosphoric acid.
  • Compound 1 is combined with about 3 to about 4 molar equivalents of phosphoric acid.
  • Compound 1 is combined with about 3 molar equivalents of phosphoric acid.
  • the solvent can contain any solvent or mixture of solvents capable of at least partially dissolving Compound 1.
  • the solvent contains an alcohol. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.
  • the solvent contains acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, 1-propan
  • the solvent is a mixture of acetone, methanol and dichloromethane.
  • the solvent is about room temperature. In some embodiments, the solvent is heated to a temperature of about 50° C. In some embodiments, the temperature is from about 50° C. to about 80° C. In some embodiments, the temperature is from about 40° C. to about 60° C. In some embodiments, the temperature is from about 45° C. to about 55° C. In some embodiments, the temperature is about 45° C., about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C. or about 80° C.
  • the solvent is heated to a temperature that can induce precipitation at a practical rate.
  • precipitation is completed within about 12 to about 24 hours, but longer and shorter periods are possible depending on the choice of precipitation solvent and temperature. In some embodiments, the precipitation is completed within about 90 minutes.
  • the precipitation of the phosphoric acid salt ( ⁇ 1:3), in some embodiments, is carried out by filtering the salt from solution.
  • Compound 1 phosphoric acid salt ( ⁇ 1:3) is amorphous.
  • Different forms of the same substance have different bulk properties relating to, for example, hygroscopicity, solubility, stability, and the like.
  • Forms with high melting points often have good thermodynamic stability which is advantageous in prolonging shelf-life drug formulations containing the solid form.
  • Forms with lower melting points often are less thermodynamically stable, but are advantageous in that they have increased water solubility, translating to increased drug bioavailability.
  • Forms that are weakly hygroscopic are desirable for their stability to heat and humidity and are resistant to degradation during long storage.
  • a Compound 1 salt provided herein is crystalline.
  • crystalline or “crystalline form” is meant to refer to a certain lattice configuration of a crystalline substance. Different crystalline forms of the same substance typically have different crystalline lattices (e.g., unit cells) which are attributed to different physical properties that are characteristic of each of the crystalline forms. In some instances, different lattice configurations have different water or solvent content.
  • the different salt forms can be identified by solid state characterization methods such as by X-ray powder diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid state NMR, and the like further help identify the form as well as help determine stability and solvent/water content.
  • XRPD X-ray powder diffraction
  • Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid state NMR, and the like further help identify the form as well as help determine stability and solvent/water content.
  • An XRPD pattern of reflections is typically considered a fingerprint of a particular crystalline form. It is well known that the relative intensities of the XRPD peaks can widely vary depending on, inter alia, the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. In some instances, new peaks may be observed or existing peaks may disappear, depending on the type of the instrument or the settings. As used herein, the term “peak” refers to a reflection having a relative height/intensity of at least about 4% of the maximum peak height/intensity. Moreover, instrument variation and other factors can affect the 2-theta values.
  • peak assignments such as those reported herein, can vary by plus or minus about 0.2° (2-theta), and the term “substantially” and “about” as used in the context of XRPD herein is meant to encompass the above-mentioned variations.
  • the term “about” means ⁇ 10%. In some embodiments, the term “about” means ⁇ 5%.
  • the salts described herein are substantially isolated.
  • substantially isolated is meant that the salt is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the salts described herein.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the salts described herein, or salt thereof. Methods for isolating salts are routine in the art.
  • Salts of the invention can also include all isotopes of atoms occurring in the final salts or Compound 1.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • the salts can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
  • solvents e.g., hydrates and solvates
  • phrases “pharmaceutically acceptable” is employed herein to refer to those salts, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • reaction temperatures will depend on, for example, the melting and boiling points of the reagents and solvent, if present; the thermodynamics of the reaction (e.g., vigorously exothermic reactions may need to be carried out at reduced temperatures); and the kinetics of the reaction (e.g., a high activation energy barrier may need elevated temperatures).
  • ambient temperature and “room temperature” or “rt” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the salt forming reaction is carried out, for example, a temperature from about 20° C. to about 30° C.
  • the salt forming reactions described herein can be carried out in air or under an inert atmosphere.
  • reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan.
  • Salts of the present disclosure can inhibit the activity of PD-1/PD-L1 protein/protein interaction and, thus, are useful in treating diseases and disorders associated with activity of PD-1 and the diseases and disorders associated with PD-L1 including its interaction with other proteins such as PD-1 and B7-1 (CD80).
  • the salts of the present disclosure are useful for therapeutic administration to enhance, stimulate and/or increase immunity in cancer, chronic infection or sepsis, including enhancement of response to vaccination.
  • the present disclosure provides a method for inhibiting the PD-1/PD-L1 protein/protein interaction.
  • the method includes administering to an individual or a patient a salt of Compound 1, or of a salt as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the salts of the present disclosure can be used alone, in combination with other agents or therapies or as an adjuvant or neoadjuvant for the treatment of diseases or disorders, including cancer or infection diseases.
  • any of the salts of the disclosure including any of the embodiments thereof, may be used.
  • the salts of the present disclosure inhibit the PD-1/PD-L1 protein/protein interaction, resulting in a PD-1 pathway blockade.
  • the blockade of PD-1 can enhance the immune response to cancerous cells and infectious diseases in mammals, including humans.
  • the present disclosure provides treatment of an individual or a patient in vivo using a salt of Compound 1 such that growth of cancerous tumors is inhibited.
  • a salt of Compound 1, or a salt as recited in any of the claims and described herein can be used to inhibit the growth of cancerous tumors.
  • a salt of Compound 1, or a salt as recited in any of the claims and described herein can be used in conjunction with other agents or standard cancer treatments, as described below.
  • the present disclosure provides a method for inhibiting growth of tumor cells in vitro.
  • the method includes contacting the tumor cells in vitro with a salt of Compound 1, or of a salt as recited in any of the claims and described herein.
  • the present disclosure provides a method for inhibiting growth of tumor cells in an individual or a patient. The method includes administering to the individual or patient in need thereof a therapeutically effective amount of a salt of Compound 1, or of a salt as recited in any of the claims and described herein.
  • a method for treating cancer includes administering to a patient in need thereof, a therapeutically effective amount of a salt of Compound 1, or a salt as recited in any of the claims and described herein.
  • cancers include those whose growth may be inhibited using salts of the disclosure and cancers typically responsive to immunotherapy.
  • the present disclosure provides a method of enhancing, stimulating and/or increasing the immune response in a patient.
  • the method includes administering to the patient in need thereof a therapeutically effective amount of a salt of Compound 1, or a salt or composition as recited in any of the claims and described herein.
  • cancers that are treatable using the salts of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic le
  • cancers treatable with salts of the present disclosure include melanoma (e.g., metastatic malignant melanoma, cutaneous melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer (e.g., breast invasive carcinoma), colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer (e.g., squamous cell carcinoma of the head and neck), urothelial cancer (e.g., bladder cancer, nonmuscle invasive bladder cancer (NMIBC)) and cancers with high microsatellite instability (MSI high ). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the salts of the disclosure.
  • melanoma e.g., metastatic malignant melanoma, cutaneous melanoma
  • renal cancer e
  • cancers that are treatable using the salts of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and
  • cancers that are treatable using the salts of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, biliary tract cancer, triple negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinal cancer, islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, sinus cancer, spinal cancer, tongue
  • the salts of the present disclosure can be used to treat sickle cell disease and sickle cell anemia.
  • diseases and indications that are treatable using the salts of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.
  • Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL) and multiple myeloma (MM).
  • ALL acute lymphoblastic leukemia
  • AML acute mye
  • Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma.
  • Exemplary lung cancers include non-small cell lung cancer (NSCLC) (e.g., squamous cell NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.
  • NSCLC non-small cell lung cancer
  • small cell lung cancer e.g., squamous cell NSCLC
  • bronchogenic carcinoma squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma
  • alveolar (bronchiolar) carcinoma bronchial adenoma
  • chondromatous hamartoma chondromatous hamartoma
  • mesothelioma mesothelioma
  • Exemplary gastrointestinal cancers include cancers of the esophagus (carcinoma, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma, adenocarcinoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer (e.g., colorectal adeno
  • Exemplary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).
  • the cancer is a urological cancer (e.g., papillary kidney carcinoma, testicular germ cell cancer, chromophobe renal cell carcinoma, clear cell renal carcinoma, or prostate adenocarcinoma).
  • liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.
  • Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors.
  • osteogenic sarcoma osteosarcoma
  • fibrosarcoma malignant fibrous histiocytoma
  • chondrosarcoma chondrosarcoma
  • Ewing's sarcoma malignant lymphoma
  • multiple myeloma malignant giant cell tumor chordoma
  • osteochronfroma osteocar
  • Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.
  • skull osteoma, hemangioma, granuloma, xanthoma, osteitis de
  • Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, serous adenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).
  • endometrial carcinoma endometrial carcinoma
  • cervix cervical carcinoma, pre-tum
  • Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma (e.g., cutaneous squamous cell carcinoma), Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.
  • diseases and indications that are treatable using the salts of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.
  • PD-1 pathway blockade with salts of the present disclosure can also be used for treating infections such as viral, bacteria, fungus and parasite infections.
  • the present disclosure provides a method for treating infections such as viral infections. The method includes administering to a patient in need thereof, a therapeutically effective amount of a salt of Compound 1, or a salt as recited in any of the claims and described herein.
  • viruses causing infections treatable by methods of the present disclosure include, but are not limited to, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome virus, ebola virus, and measles virus.
  • viruses causing infections treatable by methods of the present disclosure include, but are not limited to, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus, tuberculosis and arboviral encephalitis virus.
  • herpes virus e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus
  • adenovirus e.g., adenovirus
  • the present disclosure provides a method for treating bacterial infections.
  • the method includes administering to a patient in need thereof, a therapeutically effective amount of a salt of Compound 1, or a salt as recited in any of the claims and described herein.
  • pathogenic bacteria causing infections treatable by methods of the disclosure include chlamydia , rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella , bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.
  • the present disclosure provides a method for treating fungus infections.
  • the method includes administering to a patient in need thereof, a therapeutically effective amount of a salt of Compound 1, or a salt as recited in any of the claims and described herein.
  • pathogenic fungi causing infections treatable by methods of the disclosure include Candida ( albicans, krusei, glabrata, tropicalis , etc.), Cryptococcus neoformans, Aspergillus ( fumigatus, niger , etc.), Genus Mucorales ( mucor, absidia, rhizophus ), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • the present disclosure provides a method for treating parasite infections.
  • the method includes administering to a patient in need thereof, a therapeutically effective amount of a salt of Compound 1, or a salt as recited in any of the claims and described herein.
  • pathogenic parasites causing infections treatable by methods of the disclosure include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi , and Nippostrongylus brasiliensis.
  • the present disclosure provides a method for treating neurodegenerative diseases or disorders.
  • the method includes administering to a patient in need thereof, a therapeutically effective amount of a salt of Compound 1, or a salt as recited in any of the claims and described herein.
  • neurodegenerative diseases or disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease, Motor neurone diseases, Spinocerebellar ataxia and Spinal muscular atrophy.
  • salts of Compound 1, or any of the embodiments thereof may possess satisfactory pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolism and pharmacokinetic properties, solubility, and permeability. It will be understood that determination of appropriate biopharmaceutical properties is within the knowledge of a person skilled in the art, e.g., determination of cytotoxicity in cells or inhibition of certain targets or channels to determine potential toxicity.
  • mice refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • terapéuticaally effective amount refers to the amount of active salt that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to one or more of (1) inhibiting the disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • the salts of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • Salts of the present disclosure can be used in combination with one or more immune checkpoint inhibitors for the treatment of diseases, such as cancer or infections.
  • immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD122, CD96, CD73, CD47, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TIGIT, CD112R, VISTA, PD-1, PD-L1 and PD-L2.
  • immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD122, CD96, CD73, CD47, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG
  • the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137 (4-1BB).
  • the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA.
  • the salts provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGF beta inhibitors.
  • the salts provided herein can be used in combination with one or more agonists of immune checkpoint molecules, e.g., OX40, CD27, GITR, and CD137 (also known as 4-1B).
  • one or more agonists of immune checkpoint molecules e.g., OX40, CD27, GITR, and CD137 (also known as 4-1B).
  • the agonist of an immune checkpoint molecule is an agonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7/8, and CD137 (also known as 4-1B).
  • the agonist of CD137 is urelumab. In some embodiments, the agonist of CD137 is utomilumab.
  • the agonist of an immune checkpoint molecule is an agonist of CD40.
  • the agonist of CD40 is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or Chi Lob 7/4.
  • the agonist of an immune checkpoint molecule is an agonist of ICOS.
  • the agonist of ICOS is GSK-3359609, JTX-2011, or MEDI-570.
  • the agonist of an immune checkpoint molecule is an agonist of CD28. In some embodiments, the agonist of CD28 is theralizumab.
  • the agonist of an immune checkpoint molecule is an agonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.
  • the agonist of an immune checkpoint molecule is an agonist of TLR7/8. In some embodiments, the agonist of TLR7/8 is MEDI9197.
  • the inhibitor of an immune checkpoint molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody.
  • the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, sintilimab, SHR-1210, PDR001, MGA012, PDR001, AB122, AMP-224, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042.
  • the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD1 antibody is SHR-1210.
  • Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g. urelumab, utomilumab).
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody.
  • the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), durvalumab (Imfinzi®), atezolizumab (Tecentriq®), Avelumab (Bavencio®), MSB0010718C, tislelizumab, FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, or LY3300054.
  • the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1 bispecific antibody.
  • the anti-PD-1/PD-L1 bispecific antibody is MCLA-136.
  • the inhibitor is MCLA-145.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 and CTLA-4, e.g., an anti-PD-1/CTLA-4 bispecific antibody.
  • the anti-PD-1/CTLA-4 antibody is AK104.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody.
  • the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftilagimod alpha (IMP321).
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleclumab. In some embodiments, the inhibitor of CD73 is MEDI9447.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT is OMP-31M32.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of VISTA.
  • the inhibitor of VISTA is JNJ-61610588 or CA-170.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of B7-H3.
  • the inhibitor of B7-H3 is enoblituzumab, MGD009, or 8H9.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of KIR.
  • the inhibitor of KIR is lirilumab or IPH4102.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of A2aR. In some embodiments, the inhibitor of A2aR is CPI-444.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of TGF-beta.
  • the inhibitor of TGF-beta is trabedersen, galusertinib, or M7824.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PI3K-gamma. In some embodiments, the inhibitor of PI3K-gamma is IPI-549.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CD47.
  • the inhibitor of CD47 is Hu5F9-G4 or TTI-621.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CD70.
  • the inhibitor of CD70 is cusatuzumab or BMS-936561.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of TIM3, e.g., an anti-TIM3 antibody.
  • the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.
  • the agonist of an immune checkpoint molecule is an agonist of GITR, e.g., an anti-GITR antibody.
  • the agonist is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, or MEDI6469.
  • the agonist of an immune checkpoint molecule is an agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.
  • OX40 e.g., OX40 agonist antibody or OX40L fusion protein.
  • the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, BMS-986178, or 9B12.
  • the OX40L fusion protein is MEDI6383.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody.
  • the anti-CD20 antibody is obinutuzumab or rituximab.
  • the salts of the present disclosure can be used in combination with bispecific antibodies.
  • one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGF ⁇ receptor.
  • the bispecific antibody binds to PD-1 and PD-L1.
  • the bispecific antibody that binds to PD-1 and PD-L1 is MCLA-136.
  • the bispecific antibody binds to PD-L1 and CTLA-4.
  • the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.
  • the salts of the disclosure can be used in combination with one or more metabolic enzyme inhibitors.
  • the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase.
  • IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.
  • the additional compounds, inhibitors, agents, etc. can be combined with the present salt in a single or continuous dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.
  • Cancer cell growth and survival can be impacted by dysfunction in multiple biological pathways.
  • Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) may reduce the likelihood of drug-resistance arising in a cell population, or reduce the toxicity of treatment.
  • the salts of the present disclosure can be used in combination with one or more other therapies for the treatment of diseases, such as cancer or infections.
  • diseases and indications treatable with combination therapies include those as described herein.
  • cancers include solid tumors and non-solid tumors, such as liquid tumors, blood cancers.
  • infections include viral infections, bacterial infections, fungus infections or parasite infections.
  • the salts of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK, TGF- ⁇ R, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGF ⁇ R, PDGF ⁇ R, PI3K (alpha, beta, gamma, delta, and multiple or selective), CSF1R, KIT, FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR/Flt2, Flt4,
  • the salts of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infections.
  • inhibitors that can be combined with the salts of the present disclosure for treatment of cancer and infections include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., pemigatinib (INCY54828), INCB62079), an EGFR (also known as ErB-1 or HER-1) inhibitor (e.g., erlotinib, gefitinib, vandetanib, orsimertinib, cetuximab, necitumumab, or panitumumab), a VEGFR inhibitor or pathway blocker (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetani
  • FGFR inhibitor
  • the salts of the present disclosure can be combined with a TLR7 agonist (e.g., imiquimod).
  • a TLR7 agonist e.g., imiquimod
  • the salts of the present disclosure can further be used in combination with other methods of treating cancers, for example by chemotherapy, irradiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy or surgery.
  • immunotherapy include cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine, monoclonal antibody, bispecific or multi-specific antibody, antibody drug conjugate, adoptive T cell transfer, Toll receptor agonists, STING agonists, RIG-I agonists, oncolytic virotherapy and immunomodulating small molecules, including thalidomide or JAK1/2 inhibitor, PI3K ⁇ inhibitor and the like.
  • the salts can be administered in combination with one or more anti-cancer drugs, such as a chemotherapeutic agent.
  • chemotherapeutics include any of abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine,
  • anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4 (e.g., ipilimumab), 4-1BB (e.g., urelumab, utomilumab), antibodies to PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF- ⁇ , etc.).
  • trastuzumab Herceptin
  • CTLA-4 e.g., ipilimumab
  • 4-1BB e.g., urelumab, utomilumab
  • PD-1 and PD-L1 antibodies to cytokines (IL-10, TGF- ⁇ , etc.
  • antibodies to PD-1 and/or PD-L1 that can be combined with salts of the present disclosure for the treatment of cancer or infections such as viral, bacteria, fungus and parasite infections include, but are not limited to nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab and SHR-1210.
  • the salts of the present disclosure can further be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants or therapeutic antibodies.
  • the salts of Compound 1, or a salt as recited in any of the claims and described herein, can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines.
  • tumor vaccines include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.
  • the salts of Compound 1, or a salt as recited in any of the claims and described herein, can be used in combination with a vaccination protocol for the treatment of cancer.
  • the tumor cells are transduced to express GM-CSF.
  • tumor vaccines include the proteins from viruses implicated in human cancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV).
  • the salts of the present disclosure can be used in combination with tumor specific antigen such as heat shock proteins isolated from tumor tissue itself.
  • the salts of Compound 1, or a salt as recited in any of the claims and described herein can be combined with dendritic cells immunization to activate potent anti-tumor responses.
  • the salts of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effectors cells to tumor cells.
  • the salts of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.
  • the salts of the present disclosure can be used in combination with bone marrow transplant for the treatment of a variety of tumors of hematopoietic origin.
  • the salts of Compound 1, or a salt as recited in any of the claims and described herein, can be used in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self antigens.
  • pathogens for which this therapeutic approach may be particularly useful include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to, HIV, Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa.
  • Viruses causing infections treatable by methods of the present disclosure include, but are not limited to human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
  • human papillomavirus influenza, hepatitis A
  • Pathogenic bacteria causing infections treatable by methods of the disclosure include, but are not limited to, chlamydia , rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella , bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.
  • Pathogenic fungi causing infections treatable by methods of the disclosure include, but are not limited to, Candida ( albicans, krusei, glabrata, tropicalis , etc.), Cryptococcus neoformans, Aspergillus ( fumigatus, niger , etc.), Genus Mucorales ( mucor, absidia, rhizophus ), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • Candida albicans, krusei, glabrata, tropicalis , etc.
  • Cryptococcus neoformans Aspergillus ( fumigatus, niger , etc.)
  • Genus Mucorales mucor, absidia, rhizophus
  • Sporothrix schenkii Blastomyces dermatitidis
  • Pathogenic parasites causing infections treatable by methods of the disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi , and Nippostrongylus brasiliensis.
  • more than one pharmaceutical agent When more than one pharmaceutical agent is administered to a patient, they can be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents).
  • the salts of the present disclosure can be administered in the form of pharmaceutical compositions.
  • the present disclosure provides a composition comprising a salt of Compound 1, or a salt as recited in any of the claims and described herein, or any of the embodiments thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is indicated and upon the area to be treated.
  • Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, e.g., by a continuous perfusion pump.
  • compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, the salt of the present disclosure, in combination with one or more pharmaceutically acceptable carriers or excipients.
  • the composition is suitable for topical administration.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, e.g., a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, e.g., up to 10% by weight of the active salt, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • the active salt can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active salt is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active salt is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
  • the salts of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.
  • Finely divided (nanoparticulate) preparations of the salts of the invention can be prepared by processes known in the art see, e.g., WO 2002/000196.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one salt described herein.
  • SMCC silicified microcrystalline cellulose
  • the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w/w.
  • the composition is a sustained release composition comprising at least one salt described herein, and at least one pharmaceutically acceptable carrier or excipient.
  • the composition comprises at least one salt described herein, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose and polyethylene oxide.
  • the composition comprises at least one salt described herein, and microcrystalline cellulose, lactose monohydrate and hydroxypropyl methylcellulose.
  • the composition comprises at least one salt described herein, and microcrystalline cellulose, lactose monohydrate and polyethylene oxide.
  • the composition further comprises magnesium stearate or silicon dioxide.
  • the microcrystalline cellulose is Avicel PH102TM.
  • the lactose monohydrate is Fast-flo 316TM.
  • the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M PremierTM) and/or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel KOOLVTM).
  • the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105TM).
  • a wet granulation process is used to produce the composition. In some embodiments, a dry granulation process is used to produce the composition.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. In some embodiments, each dosage contains about 10 mg of the active ingredient. In some embodiments, each dosage contains about 50 mg of the active ingredient. In some embodiments, each dosage contains about 25 mg of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the components used to formulate the pharmaceutical compositions are of high purity and are substantially free of potentially harmful contaminants (e.g., at least National Food grade, generally at least analytical grade, and more typically at least pharmaceutical grade).
  • the composition is preferably manufactured or formulated under Good Manufacturing Practice standards as defined in the applicable regulations of the U.S. Food and Drug Administration.
  • suitable formulations may be sterile and/or substantially isotonic and/or in full compliance with all Good Manufacturing Practice regulations of the U.S. Food and Drug Administration.
  • the active salt may be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the salt actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual salt administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms and the like.
  • the therapeutic dosage of a salt of the present invention can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the salt, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a salt of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the salts of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the salt for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the salt selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a salt of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a salt of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, e.g., about 0.1 to about 1000 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the salts and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • Topical formulations can contain one or more conventional carriers.
  • ointments can contain water and one or more hydrophobic carriers selected from, e.g., liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and the like.
  • Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g., glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol.
  • Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, e.g., glycerol, hydroxyethyl cellulose, and the like.
  • topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2 or at least about 5 wt % of the salt of the invention.
  • the topical formulations can be suitably packaged in tubes of, e.g., 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8.
  • the therapeutic dosage of a salt of the present invention can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the salt, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a salt of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the salts of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the salt for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the salt selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the salts of the present disclosure can further be useful in investigations of biological processes in normal and abnormal tissues.
  • another aspect of the present invention relates to labeled salts of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating PD-1 or PD-L1 protein in tissue samples, including human, and for identifying PD-L1 ligands by inhibition binding of a labeled compound.
  • the present invention includes PD-1/PD-L1 binding assays that contain such labeled salts.
  • the present invention further includes isotopically-substituted salts of the disclosure.
  • An “isotopically-substituted” salt is a salt of the invention where one or more atoms are replaced or substituted by an atom having the same atomic number but a different atomic mass or mass number, e.g., a different atomic mass or mass number from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • a “radio-labeled” salt is a salt that has incorporated at least one isotope that is radioactive (e.g., radionuclide).
  • Suitable radionuclides that may be incorporated in salts of the present invention include but are not limited to 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled salts will depend on the specific application of that radio-labeled salt. For example, for in vitro PD-L1 protein labeling and competition assays, salts that incorporate 3 H, 14 C, 82 Br, 125 , 131 I, 35 S or will generally be most useful. For radio-imaging applications 11 C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br will generally be most useful.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 I, 35 S and 82 Br. Synthetic methods for incorporating radio-isotopes into organic compounds and salts are known in the art.
  • a labeled salt of the invention can be used in a screening assay to identify and/or evaluate compounds.
  • a newly synthesized or identified salt i.e., test salt
  • a test salt which is labeled can be evaluated for its ability to bind a PD-L1 protein by monitoring its concentration variation when contacting with the PD-L1 protein, through tracking of the labeling.
  • a test salt (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to a PD-L1 protein (i.e., standard compound). Accordingly, the ability of a test salt to compete with the standard compound for binding to the PD-L1 protein directly correlates to its binding affinity.
  • the standard salt is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test salt, and the relative binding affinity of the test salt is thus ascertained.
  • kits useful useful, e.g., in the treatment or prevention of diseases or disorders associated with the activity of PD-L1 including its interaction with other proteins such as PD-1 and B7-1 (CD80), such as cancer or infections, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a salt of Compound 1, or any of the embodiments thereof.
  • kits can further include one or more of various conventional pharmaceutical kit components, such as, e.g., containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • X-Ray Powder Diffraction analysis was carried out on a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD) instrument.
  • the general experimental procedures for XRPD were: (1) X-ray radiation from copper at 1.054056 ⁇ with K ⁇ filter; (2) X-ray power at 30 KV, 15 mA; and (3) the sample powder was dispersed on a zero-background sample holder.
  • the general measurement conditions for XRPD were: Start Angle 3 degrees; Stop Angle 45 degrees; Sampling 0.02 degrees; and Scan speed 2 degree/min.
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric analysis
  • Thermogravimetric analysis was carried out on a TA Instrument Thermogravimetric Analyzer, Model Q500.
  • the general experimental conditions for TGA were: ramp from 20° C.-600° C. at 20° C./min; nitrogen purge, gas flow at 40 mL/min followed by balance of the purge flow; sample purge flow at 60 mL/min; platinum sample pan.
  • the solution (slightly turbid) was polish filtered directly into a 60 mL addition funnel using a syringe and filter disks.
  • the round bottom flask was rinsed with 6 mL 10% methanol/dichloromethane solution and the solution was filtered into the addition funnel.
  • the Compound 1 solution was added over 29 minutes.
  • the addition funnel was rinsed with 4 mL 10% methanol/dichloromethane, and added to the slurry. The slurry was stirred for 90 minutes at room temperature.
  • the stoichiometric ratio between Compound 1 and hydrobromic acid was determined as 1:1 by HPLC.
  • Compound 1 mono-hydrobromic acid salt was characterized by XRPD ( FIG. 1 ). Analytical data collected on the product were obtained. The purity of the mono-hydrobromic acid salt was determined by HPLC as 99.4%.
  • the stoichiometric ratio between Compound 1 and hydrobromic acid was determined as 1:1 by HPLC.
  • Compound 1 mono-hydrobromic acid salt was characterized by XRPD ( FIG. 2 ). Analytical data collected on the product were obtained. The purity of the mono-hydrobromic acid salt was determined by HPLC as 99.7%.
  • Oxalic acid (7.41 mg, 0.082 mmol, 1.05 eq.) was added to a solution of Compound 1 (54.36 mg, 0.076 mmol, 1.0 eq.) in tetrahydrofuran (2.0 mL).
  • the reaction mixture was stirred to give a slurry.
  • the slurry was stirred for 2 h, and filtered to give a mother liquid and a solid.
  • the solid was dried under vacuum at 40-41° C. overnight to provide Compound 1 mono-oxalic acid salt as an amorphous solid (54.5 mg, 89% yield).
  • the stoichiometric ratio between Compound 1 and oxalic acid was determined as 1:1 by elemental analysis (calculated for C 43 H 41 N 7 O 8 .2H 2 O: C, 62.99; H, 5.53; N, 11.96 and analysis found C, 62.48; H, 5.33; N, 11.44).
  • Compound 1 mono-oxalic acid salt was characterized by XRPD ( FIG. 3 ). TGA of the salt is provided in FIG. 4 . Analytical data collected on the product were obtained. The purity of the mono-oxalic acid salt was determined by HPLC as 99.3%.
  • the Compound 1 solution was polish filtered directly into a clean scintillation vial using a syringe and filter disks.
  • the Compound 1 solution was added dropwise over 3 minutes via pipet.
  • the slurry was stirred for 90 minutes at room temperature, and the solids were filtered.
  • the filter cake was rinsed with acetone (10 mL), and the solids were dried under high vacuum for 18 hours. 565 mg of product was recovered having a purity 98.58%
  • the stoichiometric ratio between Compound 1 and hydrochloric acid was determined as 1:1 by HPLC.
  • Compound 1 mono-hydrochloric acid salt was characterized by XRPD ( FIG. 5 ). Analytical data collected on the product were obtained. The purity of the mono-hydrochloric acid salt was determined by HPLC as 99.0%.
  • the stoichiometric ratio between Compound 1 and hydrobromic acid was determined as 1:2 by HPLC (sample 2).
  • Compound 1 di-hydrobromic acid salt was characterized by XRPD ( FIG. 8 , samples 1 and 2). Analytical data collected on the product were obtained. The purity of the di-hydrobromic acid salt was determined by HPLC as 97.8% (sample 1) and 97.2% (sample 2).
  • the stoichiometric ratio between Compound 1 and hydrobromic acid was determined as 1:2 by HPLC.
  • Compound 1 di-hydrobromic acid salt was characterized by XRPD ( FIG. 9 ). Analytical data collected on the product were obtained. The purity of the di-hydrobromic acid salt was determined by HPLC as 99.7%.
  • Oxalic acid (20.11 mg, 0.223 mmol, 2.05 eq.) was added to a solution of Compound 1 (75.58 mg, 0.109 mmol, 1.0 eq.) in tetrahydrofuran (2.0 mL). The reaction mixture was stirred to give a slurry. The slurry was stirred continuously for 2 h, and filtered to give a mother liquid and a solid. The solid was dried under vacuum at 40-41° C. overnight to provide Compound 1 di-oxalic acid salt (89.5 mg, 94% yield) as a crystalline solid.
  • the stoichiometric ratio between Compound 1 and oxalic acid was determined as 1:2 by elemental analysis (calculated for C 45 H 43 N 7 O 12 ; C, 61.85; H, 4.96; N, 11.22 and analysis found C, 60.91; H, 5.21; N, 10.73).
  • the crystallinity of the di-oxalic acid salt was confirmed by XRPD ( FIG. 10 , Table 1) and further supported by DSC ( FIG. 11 ), indicating the salt with an onset temperature at 222.23° C. and a peak at 235.26° C. TGA of the di-oxalic acid salt is provided in FIG. 12 , and exhibited approximately 0.7% of weight loss up to about 100° C. Analytical data collected on the product were obtained. The purity of the di-oxalic acid salt was determined by HPLC as 96.10%.

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